16-alkoxy steroids and processes



United States atent 3,%8,2Z4 Patented Dec. 11, 1952 This invention relates to novel steroid compounds. More specifically, this invention relates to several related types of steroid compounds, each being a separate embodiment of our invention. More specifically, this invention relates to 16-spiroepoxy alkylidene steroids of the structure Also, it relates to compounds of 16a,l7a-epoxy-16;3- alkoxy-alkyl steroids of the formula OHzORa It also relates to 16a and fi-alkoxyalkyl steroids of the formula CH OR:

Elf 2':

as well as to and fi-alkoxymethyl pregnanes of the formula and lfl-alkanoyl pregnanes of the formula in all of these formulae, R may be keto oxygen or 3 hydroxyl, R may be hydrogen or lower alkanoyl, R may be hydrogen or alkyl, R is alkyl, X may be hydrogen or halogen, a dotted line in ring A indicates that the C -C bond may be single or double, and a wavy line joining a C substituent indicates that the substituent may be on or ,6. The first four classes of these compounds are useful as anti-inflammatory agents. The last two classes together with the compounds of the second class, namely the 16,17-epoxy-16-methoxy methyl steroids are useful as intermediates for compounds having anti-inflammatory properties as is further shown in detail in the following specifications.

The various steroids produced in accordance with the present invention possess extremely high anti-inflammatory activity, considerably greater than that of the parent steroids, and are especially efiective for the treatment of arthritis and related diseases since they can be adminis tered for their cortisone-like action in low dosage thereby minimizing undesired side effects.

Of the compounds of our invention, those having a 1,4-diene structure are prepared as described in Schematic Flow Sheet I. Among the materials which may be used as a starting material in the process described in I are Mot-methyl 1,4 pregnadiene-17a,21-diol-3,11,20-trione, l6fi-methyl 1,4 pregnadiene-l7a,21-diol-3,l1,20-trione, 16a ethyl 1,4 pregnadiene-l7a,2l-diol-3,11,20-trione, 16,8 ethyl 1,4 pregnadiene-l7a,2l-diol-3,11,20-trione, l6u-propyl 1,4 pregnadiene-l7a,21-diol-3,11,20-trione, l6B-propyl-1,4-pregnadiene-17a,21 diol 3,11,20-trione, lfia-methyl 1,4 pregnadiene 11 3,17a,21 triol-3,20- dione, 16/8 methyl 1,4 pregnadiene-l1fi,17u,21-triol- 3,20-dione, 16 x-ethyl 1,4 pregnadiene-l1fl ,l7a,21-triol- 3,20-dione, 16,6-ethy1 1,4 pregnadiene-l1/5 ,l7a,21-trio1- 3,20-dione, 16oz-bl1ty1 1,4 pregnadiene-ll ,6,l7a,21-triol- 3,20-dione, 16/8 butyl-1,4-pregnadiene-l 1B,17oc,21-tri01-3, ZO-dione, 9-halo-l6alkyl 1,4 pregnadiene-l7a,21-diol-3, 11,20-trione, 9u-fluoro-l 6a-butyl- 1 ,4-pregnadiene-l 611,21-

diol-3,1 1,20-trione, 9u-fluoro-1oa-methyl-lA-pregnadiene- OHzOAc )=NHNHOONHa R1 irCHzRa 4-pregnadiene-11B,17a,21-triol-3,20-dione, 9oz fluoro-16abutyl-1,4-pregnadiene-11,8,17a,21-triol-3,20-dione, 9u-fluor0465 butyl-lA-pregnadiene-l 1 ,8,17a,21-trio1-3,20-dione, and the like.

Those compounds of our invention having only one double bond in ring A, in the A position, are prepared by partial hydrogenation of the corresponding A compounds or from ring A saturated intermediates as described in Schematic Flow Sheet II. Among the starting materials which may be used in the process of II may be mentioned 3u-acetoxy 16 pregnene-11,20-dione, Sat-acetoxy-16-allopregnene-11,20-dione, and the like. This route can also be used to prepare the A compounds by SeO oxidation of ring A (before or after the A double bond is introduced as shown in Flow Sheet II).

The details of the reactions shown in Tables 1 and 2 are to be found in the examples.

=Chr0mat0graphic separation of isomers =Diazomethane plus fluoroforic acid in inert solvent such as methylene chloride. Higher diazo alkanes introduce a higher alkyl group, such as ethyl from diazoethane, etc.

==Catalytic hydrogenation =Reintroduction of ring A double bonds (SeO: or

bromination-dehydrobromination) =Strong acid (e.g., HBr etc.) at 50 C.

=Acid or base hydrolysis =Cata1ytic hydrogenation over Pd to one mole H,

uptake CH: H: 10 #9, ,N:

I l AcO-C & a "C *4 CH: H:

' 6o {1 mg mo 50 J10 I '--OH (I) Ton-R, Forum C AcOQ then G) 1701,21-dihydroXy-16a and [3- l-methoxyethyl) -1,4pregnadiene-3,11,20-trione 1701,21-dihydroxy-1601 and ;3-( l-methoxypropyl)-1,4-pre,,-

nadiene-3,11,20-trione 1701,21-dihydroxy-16o1 and 5- l-methoxybutyl) -1,4-pregnadiene-3,11,20-trione 1701,21-dihydroxy-1601 and fi-methoxymethyl-4-pregnene- 3 ,11-20-trione 1701,21-dihydroxy-1601 and nene-3 ,11,20-trione 1701,21-dihydroXy-1601 and 8-(1-methoXypr0pyl) -4-pregnene-3,11,20-trione 1701,21-dihydroXy-16o1 and /3(1-rnethoXybutyl)-4-pregene-3 ,11,20-trione 1 15,1701,21-trihydrxy-1601 and ,Bmethoxymethyl-1-4-pregnadiene-3 ,ZO-dione 11fi,1701,21-trihydroxy-1601 and 5- 1-methoxyethyl)-1,4-

pregnadiene-3 ,ZO-dione 11fi,1701,21-trihydroXy-1 601 and ,8-(1-methoxypropyl)1,4-

pregnadiene-3 ,ZO-dione 116,1701,21-trihydroXy-16a pregnadiene-3 ,ZO-dione 11{3,1701,21-trihydroxy-1601 Irene-3 ,ZO-dione 11f3,17o1,21-trihydroXy-161x pregnene-3 ,20-di0ne 11B,1701,21-trihydroxy-1611 pregnene-3 ,ZO-dione 11[3,1701,21-trihydroxy-1601 pregnene-3 ,20-dione as Well as the corresponding 16-(1-ethoxy alkyl),(1-propoxyalkyl),(1-butoxy alkyl) etc. compounds.

Another group of compounds which are potent antiinflammatory agents includes such compounds as 901-fluoro-1701,2l-dihydroxy-16a and ,B-methoxymethyl- 1,4-pregnadiene-3 ,11,20-trione 901-fluoro- 17 01,21-dihydroXy-1601 and {3-( l-methoxyethyl) 1,4-pregnadiene-3 ,11,20-trione 901-fiuoro- 1 711,2 l-dihydroxy-l 601 and [3- l-methoxypro pyl) 1 ,4-pre gnadiene-3 ,11,20-trione 901-f1uoro-1701,21-dihydroxy-1601 and pl-methoxybutyl) 1,4-pregnadiene-3 ,11,20-trione 901-fluoro-1701,21-dihydroXy-1601 and ,B-rnethoxymethyl- 4-pregnene-3,11-20-trione 901-fiuoro-1701,21-dihydroxy-1601 and B-( l-methoxyethyl) 4-pregnene-3 ,1 1,20-trione 901fluor0-1701,21-dihydroxy-1601 and ,B- l-methoxypropyl) -4-pregnene-3 ,11,20-trione 901-fiuoro-1701,2 l-dihydroxy- 1 601 and p-(1-methoxybuty1)- 4-pregnene-3,11,20-trione 901-fluoro-1 1p, 1701,21-trihydroxy-1601 and fl-methoxymethyl-1-4-pregnadiene-3 ,20-dione 901-fluoro-11[3,1701,21-trihydroXy-1601 and ,B-( l-methoxyethyl) -1,4-pregnadiene-3 ,20-dione 901-fluoro-115,1701,21-trihydroXy-1601 and /8-( 1-methoxy propyl) -1,4-pregnadiene-3 ,20-dione 901-fluoro-115,1701,21-trihydroxy-1601 and B-( l-methoxy butyl -1,4-pregn adiene-3 ,ZO-dione 901-fluoro-11fi,1701,21-trihydroxy-1601-and B-methoxymethy1-4-pregnene-3 ,ZO-dione 91:1-fiuoro-11(3,1701,21-trihydroxy-1601 and B-(1-methoXyethyl) -4-pregnene-3 ,20-dione 901-fluoro-11B,1701,21-trihydroxy-1601 and ,B-( l-methoxypropyl -4-pregnene-3 ,20-dione 901-fluoro-11B,1701,21-trihydroxy-1601 and 5- l-methoxybutyl) -4-pregnene-3 ,ZO-dione 9a-brom0-171x,21-dihydroXy-1601 and ,G-methoxymethyl- 1 4-pregnadiene-3 ,11,20-trione 901-brorno-1701,21-dihydr0xy-1601 and 5-methoxymethy1-4- pregnene-3 ,11,20-trione 901-brorno-11B,1701,21-trihydroxy-1601 and ,B-methoxymethyl-1,4-pregnadiene-3 ,20-dione 901-bromo-11B,1701,21-trihydroxy-161x and fi-methoxymethyl-4-pregnene-3,ZO-dione ,B-( 1-methoXyethy1)-4-pregand ,8- 1-methoxybutyl)-1,4-

and fi-methoxymethylt-pregand 5-(1-methoxyethyD-4- and p-(1-methoxypropyD-4- d ,3-(1-methoXybutY 16 91x-chloro-1701,21-dihydroXy-16o1, and ,B-methoxymethyl-l,

4-pregnadiene-3 ,11,20-trione 901-ch1oro-1701,21-dihydroxy-1601 and ,B-methoxymethyl- 4-pregnene-3,11-20-trione 901-ehloro-11fl,1711,21-trihydroxy-1601 and ,B-methoxymethyl-1,4-pregnadiene-3,20-dione 901-c'nl0ro-11fi,1701,21-trihydroxy-1601 and ,B-methoxymethyl-4-pregnene-3,20-dione and the 21 acetates, propionates and butyrates of each of the above compounds, as well as the corresponding 16(1-ethoxy alkyl), (l-propoxyalkyl), (l-butoxyalkyl) etc. compounds.

A group of compounds which are important intermediates in the preparation of many of the anti-inflammatory agents described above include such compounds as 3 01,1701-dihydroxy-1601 and B-methoxymethyl-pregnane- 1 1,20-dione 3 01,1701-dihydroxy-1601-( l-methoxyethyl)-pregnane-11,20-

dione 3 01,1701-dihydroXy-1601-( l-rnethoxypropyl) -pregnane- 1 1,20-dione 3 01,1701-dihydroxy-1601-( l-methoxybutyl) -pregnane- 1 1,20-dione 3 01,1 1,8, 1701-trihydroxy-1 60. and ,B-methoxymethylpregnane-11,20-one 3 01,1 1B,1701-trihydroXy-161z(l-methoxyethyl)-pregnane- 11,20-one 3 01,11B,1701-trihydroxy-1601-(1-methoxypropyl)-pregnane- 1 1 ,20-one 301,11,18,1701-trihydroxy-1601-(l-methoxybutyD-pregnane- 1 1,20-one.

Another group which are important intermediates for anti-inflammatory agents are such compounds as 3 01,1701-dihydroXy-16B-forrnyl-pregnane-11,20-dione 3 01,1701-dihydroxy-16(3-acetyl-pregnane-11,20-dione 3 01,1701-dihydr0xy-16fi-propionyl-pregnane-11,2O-dione 3 01,l701-dihydroxy-16B-butyryl-pregnane-11,20-di0ne 3 01,11/3,1701-trihydroxy-16,8-formyl-pregnane-11,20-one 301,11,8,1701-trihydroxy-16,8-acetyl-pregnane-11,2O-one 3 01,1 113,171x-trihydroxy-16B-propiony1-pregnane-1 1,20-one 3 01,1 ,1701-trihydroXy-16fi-butyryl-pregnane-l1,20-one 17o1,2 1 -dihydroxy- 1 G-spiroepoxybutylidenyl-1 ,4-pregnadience-3,11,20-trione 1701,21-dihydroxy-16-spiroepoxyrnethylene-4-pregnene- 3,11,20-trione 1701,2 1-dihydroxy-16-spiroepoxyethylideny1-4-pregnene- 3,11,20-trione 17 01,2 ldihydroxy- 1 6-spiroepoxypropylidenyl-4-pregnene- 3,11,20-trione 17 01,2 1-dihydr0xy-16-spiroepoxybutylidenyl-4-pregnene- 3,11,20-tri0ne 11,8,1701,21-trihydroXy-16-spiroepoxymethylene-1,4-

pregnadiene-3 ,20-di0ne 1 1B, 1701,2l-trihydroxy-16-spiroepoxyethylideny1-1,4-

pregnadiene-3,20-dione 115,1701,21-trihydroxy-16-spiroepoxypropylidenyl-1,4-

pregnadiene-3 ,20-dione pharmaceutical practice may be employed where there is no incompatibility with the active materials. The composition may take the form of tablets, powders, capsules, eliXirs, syrups or other dosage forms which are particularly useful for oral ingestion. Liquid diluents are employed in sterile condition for parenteral use, namely, by injection. Such a medium may be a sterile solvent for the active material. For topical administration any of the known dermatologic vehicles may be employed. Such vehicles for external application include water-soluble ointment bases, oils, petrolatum and jellies.

Our invention can be illustrated by the following examples:

Example 1 A mixture of 1.00 g. of 9Dc-flll91O-11/3,].70t,21-fiihydroxy-l6a-methy1-1,4-pregnadiene-3,20-dione, 750 mg. of semicarbazide base, 280 mg. of semicarbazide hydrochloride in 20 ml. of methanol and 10 ml. of dimethyltormamide is refluxed for 20 hours under nitrogen. The mixture is cooled to 20 C. and 100 ml. of Water is added with stirring. The precipitated 3,20-disemicarbazone of 9a fluoro 11,8,17u,21 trihydroxy-16a-methyl-L4-pregnadiene-3,20-dione is filtered, Washed With water, and dried. In a similar manner are prepared the 3,20-disernicarbazone of 9tx-fluoro-11,8,17o 21-trihydroxy-l6B-methyl- 1,4-pregnadiene-3,20-dione, 3,20-disemicarbazone of 116, l7a,21-trihydroxy-l6ot-methyl-1,4-pregnadiene-3,20-dione; 3,20-disesmicarbazone of 11fi,l7a,21-trihydroxy-16/3- methyl-1,4-pregnadiene-3,20-dione; 3,20-disemicarbazone of l7a,2l-dihydroxy-l6a-methyl-1,4-pregnadiene-3,1 1,20- trione and the 3,20-disemicarbazone of l7tx,2l-dihydroxy- 16fi-methyl-1,4-pregnadiene-3 l 1,20-trione.

Example 2 CHQOAG A solution of 500 mg. of the 3,20-disemicarbazone of 9c: fluoro 11fi,17a,2l-trihydroxy-I6u-methyl-L4-pregnadiene-3,20dione in 10 ml. of acetic acid and 0.5 ml. acetic anhydride is refluxed under nitrogen for one hour to produce the corresponding 3,20-disemicarbazone of 115,21 dihydroxy 16-methyl-l,4,16-pregnatriene-3,20- dione 2l-acetate. The reaction mixture is cooled, 13 ml. of water is added and the mixture heated on the steam bath for 5 hours. It is then concentrated in vacuo nearly to dryness and water and chloroform added. The mixture is thoroughly extracted with chloroform, and the chloroform extract Washed with excess aqueous potassium bicarbonate, saturated salt solution and dried over magnesium sulfate. Chromatography of the residue on neutral alumina and crystallization of pertinent benzenechloroform fractions gives 9a-tluoro-11,6,21-dihydroxyl6-methyl-1,4,l6-pregnatriene-3,20-dione ZI-acetate.

Similar treatment of the 3,20-disemicarbazone of 9afiu oro-l 1/3, l7a,2l-trihydroxy-l dd-methyl-1,4-pregnadiene- 3,20-dione also leads to 9ot-iuoro-l1,8,21-dihydroxy-16- methyl-1,4,16-pregnatriene-3,ZO-diOne 21-acetate.

In a similar manner 115,21-dfl1ydroxy-16-methyl-1,4,16- pregnatrienel20-dione 21-acetate; and 2l-hydroxy-l6- methyl-1,4,l6-pregnatriene-3,11,20-trione 2l-acetate 9afluoro 11,8,21 dihydroxy 16 methyl-4,16-pregnadiene- Example 3 To a stirred solution or" 500 mg. of 9a-fiuoro-llfi,2ldihydroxy 16 methyl-1,4,16-pregnatriene-3,ZO-dione 21- acetate in 15 ml. of methylene chloride at 0 C. are added 8 of disodium hydrogen phosphate and 2 ml. of 2 M eroxytrifiuoroacetic acid. in methylene chloride. After 10 minutes at 0 C. and 25 for one hour, water is added and the mixture thoroughly extracted with methylene chloride.

The latter extract is Washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent and crystallization of the residue from acetone-ether gives 9cc-flt1OI0-l1/3,Z1-dihdroxy 16,8 methyl-l6a,17a-oxido-1,4-pregnadiene-3,20- dione ZI-acetate.

In a similar manner are prepared 11,6,i2l-dihydroxyl =6fi-methyl-16a, l7 tt-epoxy-1,4-pregnadiene-3,20-dione 21- acetate; 21 hydroxy-lfifi-methyl-la,l7u-epoxy-l,4-pregnadiene-3,1l,20-trione 21-acetate; 9ot-fiuoro-ll5, Zl-dihydroxy 16,8-methyl-16a,l7a'epoxy-4-pregnene-3,ZO-dione 21 acetate; 11,6,2l-dihydroxy-16,6-methyl-16a,Not-epoxy- 4-pregnene-3,20-dione ill-acetate, wd 21-hydroxy-16B- methyl-161x,l7u-epoxy-4-pregnene-3,l1,20-trione 21- acetate.

Example 4 CHqOAc A solution of 600 mg. of 9ot-flu0ro-115,2l-dihydroxy- 16fi-methyl-16a,l7m-epoxy-l,4-pregnadiene-3,20-dione 21- acetate in 18 ml. of benzene and 2.5 ml. trifluoroacetic acid is maintained at 25 C. for 18 hours. Ethyl acetate (50 ml.) is added, followed by sufiicient 5% sodium carbonate to neutralize the acid present. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated to dryness in vacuo. Crystallization of the residue from ethyl acetate leads to the desired 9ot-fluoro-11fi,17a,2l-trihydroxy 16 methylene-1,4-pregnadiene-3,20-dione 21-acetate.

In a similar manner are prepared 11fi,17a,21-trihydroxy- 1'6 methylene 1,4 pregnadiene-3,20-dione ZI-acetate; 17a.,21 dihydroxy-16-methylene-1,4-pregnadiene-3,11,20- trionc 2l-acetate; 9ot-fluoro-l1,8,17a,2l-trihydroxy-l6- methylene-4-pregnene-3,20-dione 21-acetate; 11,8,17ot,21- trihydroxy 16 methylene-4-pregnene-3,ZO-dione 21-acetate; and 17a,2l-dihydroxy-16-methylene-4-pregnene-3,11, 20-trione 21-acetate.

Alternatively, to a stirred solution of 600 mg. of afiuoro l113,2l-dihydroxy-l6fi-methyl-l6a,17a-epoxy-1,4 pregnadiene-3,20-dione 21-acetate in 2.4 ml. of tetrahy- The procedure of Example 3 is followed, using an equivalent quantity of 9a-fluoro-l1}8,17a,21-trihydroxy- 16-methy1ene-1,4-pregnadiene-3,20 dione 21-acetate (the product of Example 4) in place of the fiuoro-dihydroxymethyl pregnatriene dione acetate used there as a starting material. The product is a mixture of 9a-fiuoro-l1B,17a, 21 trihydroxy-l6-spiroepoxymethylene-1,4-pregnadiene- 3,20-dione 21-acetate and 9ot-fluoro-115,21-dihydroxy- 1604,1711 epoxy-lfi-hydroxymethyl-l,4-pregnatriene-3,20- dione 21-acetate. The mixture is separated by chromatography on g. of neutral alumina, from which the 16- spiroepoxymethylene isomer is eluted first by benzene and chloroform. This compound is useful as an anti-inflammatory agent. The isomeric 16-hydroxy-methyl 16,17 epoxy compound is used as an intermediate in further synthesis.

In a similar manner, there are prepared and isolated 11 3,17a,21-trihydroxy-16-spiroepoxymethylene-1,4 pregnadiene-3,20-dione 2.1 acetate; 170;,21 dihydroxy 16- spiroepoxymethylene-1,4-pregnadiene-3,11,20 trione 21 acetate; 9oz-fiuoro-l1/3,17a,21-trihydroxy-l6 spiroepoxymethylene-4-pregnene-3,ZO-dione 21 acetate and 1704,21- dihydroxy-16-spiroepoxymethylenel-pregnene 3,11,20- trione 21 acetate together with the isomeric 115,21-dihydroxy-l6a,l7ot-epoxy-l6-hydroxymethyl-l,4 pregnadiene- 3,20-dione 21 acetate; 2l-hydroxy-16a,17a-epoxy-l6-hydroxymethyl-1,4-pregnadiene-3,11,20 trione 21 acetate; 9m-fiuoro-1l;8,2l-dihydroxy-16a,17a-epoxy-16 hydroxymethyl-4-pregnene-3,20-dione 21 acetate; and 2l-hydroxy- 16a,17 x-epoxy-16-hydroxymethyl 4 pregnene 3,11,20- trione 21 acetate.

Example 6 CHzOAc washed with dilute aqueous potassium bicarbonate, dried over magnesium sulfate and concentrated to dryness. Crystallization of the residue from acetone and ether gives 9a-fi1l0lO-l 1p,2l-dihydroxy-16a,Hot-epoxy 1 6 methoxymethyl-1,4-pregnadiene-3,ZO-dione-Z1 acetate.

When the other 1 6a,l7oc-epoxy-16-hydroxymethyl compounds prepared in Example 5 are used in the above procedure, there are obtained the corresponding 16- methoxymethyl compounds. When diazoethane, diazopropane or diazobutane is used in place of diazomethane, the corresponding alkoxymethyl compounds are obtained.

Example 7 onioac onto Ac TQHOOHS To a stirred solution of 1.00 g. of 9a-fluoro-11p,21-dihydroxy-l6B-methoxymethyl-16a,Not-epoxy 1,4 pregnadiene-3,20-dione-2l-acetate (product of Example 6) in 15 m1. of glacial acetic acid at 15 C. is added 5 ml. of 7% hydrogen chloride in acetic acid at 15 C. (Alternatively similar results are obtained with 800 mg. of the starting compound in 5 m1, of acetone and 1 ml. of cone. HCl cooled to 10-15 C.). In either case, after 5 minutes at 1015 0., water is added and the solid product is filtered, washed with Water and dried in air to give a mixture of the corresponding A -16-methoxymethyl'17a-hydroxy and 16-methoxymethylene-17a-hydroxy steroids.

This mixture is separated into its components by chromatogrpahy on Whatman #3 filter paper (40 mg. per 6" x 20" sheet) utilizing formamide as the stationary .phase and chloroform-benzene (1:9) as the mobile phase. The appropriate band (visible under ultraviolet light) is cut out, eluted with methanol, and the methanol is concentrated to dryness in vacuo. Water is added to the residue and the solid is filtered, washed with water and dried in air. Pure crystalline material is obtained in each case by crystallization from ethyl acetate-hexane or acetone-ether, the products being respectively L-fi11OI'O-16- methoxymethylene-l1 8,l7u,2l-trihydroxy-t1,4 pregnadiene-3,20-dione-21-acetate and 9tx-fluoro 16 methoxymethyl-11 8,17a,21-trihydroxy-1,4,15-pregnatriene 3,20- dione-Zl-acetate. In practice, separation is not necessary since the next step, a reduction, will give the same product from either isomeric component.

When the various other 160:,1712 epoxy-16p methoxymethyl compounds, formed by the procedure of Example 6 from the various products of Example 5, are substituted for the epoxy compounds used as starting materials in the above process, the corresponding 16-methoxymethyl A and 16-methoxymethylene compounds are obtained.

Example 8 oHio Ac -on Torment CHzO AC do I.

-OH 110 Tornooru gen is complete in two hours. The ring A double bonds reduce before the ring D lo-methoxymethylene or A double bonds. The reaction mixture is filtered and the filtrate concentrated to dryness in vacuo to give a solid residue consisting of ldor-rnethoxymethyl and 16,8-methoxymethyl-9a-fluoro-1 lfi',l7a,2l-trihydroxyt and SB-preg nane-3,20-dione ZI-acetates.

T o 500 mg. of the mixture produced in the preceding paragraph in 30 ml. of t-amylalcohol and 0.1 ml. of the acetic acid is added 500 mg. of selenium dioxide and 500 mg. of mercury. The mixture is stirred and refluxed under nitrogen for 18 hours. 500 mg. of selenium dioxide is then added and the mixture is refluxed an additional 24 hours. The mixture is filtered and the filtrate is evaporated to dryness. The residue is taken up in ethyl acetate and washed with dilute aqueous sodium hydroxide and Water and dried over magnesium sulfate. it is then treated with activated charcoal, filtered, and the filtrate evap orated to dryness. The residue is separated into 16amethoxymethyl-9a-fluoroprednisolone 21-acetate and 16B- methoxymethyl-9a-fluoroprednisolone 21-acetate by paper chromatography as described under Example 7.

The ZI-acetates are hydrolyzed to the :free 21-alcohols by treating 1.0 g. of compound with 30 ml. of methanol and l g. of KHCO in ml. of water, under nitrogen. The mixture is refluxed 7 minutes, cooled, and neutralized With 1 ml. of acetic acid in 10 m1. of water. The methanol is removed in vacuo and the product is extracted with ethyl acetate. Evaporation of the solvent gives the free 21-hydroxy compound.

When the other compounds produced in Example 8 are used in the above procedure in place of the above starting material, there is obtained the correspondingly substituted 160a and fi-methoxymethyl A -steroid. Thus, by the procedures of Examples 1, 2, 3, 4, 5, 6 and 7, there is obtained 1lfi,l7oc,21-t1ll'lYdIOXY-l6ot and B-methoxymethyl-1,4-pregnadiene-3,20-dione; 17a,2l-dihydroxy- 160s and fi-methoxymethyl 1,4 pregnadiene 3,11,20- trione; 9u-fluoro-11fi,17u,2l-trihydroxy-l6fi and amethoxymethyl-l,4-pregnadiene-3,20-dione; and 90: fluoro- 17u,21-dihydroxy-l6a and fi-methoxymethyl-1,4-pregnadiene-3,11,20-trione Example 9 (EHgOAO 00 '---0B nof: Tonto om and onion;

' -OH 110%]: Tonto on,

ZI-acetate) is obtained by crystallization of the residue from ethyl acetate-hexane.

In a similar manner starting with the corresponding 1op-methoxymethylprednisolone analog is obtained 16,8- methoxymethyl-9a-fluorohydrocortisone 21-acetate.

Example 10 In a 50 ml. 3-11eck flask equipped with condenser, dropping funnel and nitrogen inlet are placed 20 g. of potassium hydroxide in ml. of water, ml. of methanol and 100 ml. of ether. A solution of 10 g. of N-methyl-N-nitroso-tosylamide in 50 ml. of ether is placed in the dropping funnel.

Diazomethane is generated by warming the generation flask to 4045 C. and cautiously adding the N- methyl-N-nitro-tosylamide-ether from the dropping funnel. Nitrogen is utilized to sweep the diazomethane into a solution of 20 g. of 3a-acetoxy-l6-pregnene-l1,20-dione in 106 ml. of tetrahydrofuran and ml. ether. The process is continued until the steroid solution remains yellow for several hours. The product, 30.."EIC6lOXY'16OL, 17a-methyleueazo pregnane-ILZO-dione largely precipitates from the reaction mixture. After 1.6 hours, the mixture is filtered, washed with ether and dried in air.

37.4 g. of 3a-acetoxy-16u,17a-methyleneazo-pregnane- 11,20-di0ne is placed in a 500 ml. round-bottom flask and heated by an oil bath in vacuo (pressure 0.6 mm). A manometer and 12-liter surge flask are in the line between the reaction flask and pump trap. When the bath temperature reaches 180 C. the 3a-acetoxy-l6a,17u-methyleneazo-pregnane-l1,20-dione begins to melt with evolution of nitrogen. The maximum pressure reached is 83 mm. After 10 minutes at ISO-182 C. the melt is cooled. It is taken up in about ml. of acetone, filtered through diatomaceous earth, concentrated to about 100 ml., and ether is slowly added to the boiling solution until crystallization occurs. The product is 3a-acetoxy-16-methyl-16- pregnene-l 1,20-dione.

Similarly, when 3a-acetoxy-16-allopregnene-11,20- dione is used in place of the acetoxy pregnene-dione, the corresponding acetoxy-l6-methyl-16-allopregnene is obtained.

Example 11 filtered, washed with water, and dried in air and in vacuum. The product is 16a,l7a-epoxy3a-hydr0xy-l6,B methyl-pregnane-l1,20-dione which is acetylated at -3 by treatment with m1. of acetic anhydride and ml. of pyridine at for 18 hours. The product 16a,17aepoxy-3a-acetoxy-16(3-methyl-pregnane-11,20-dione is isolated by addition of water. It is filtered, washed with water and dried in air.

When the acetoxy-16-methyl-l6-allopregnene is used instead of the pregnene above, the corresponding 16oz, 17a-epoxy compound is obtained.

Example 12 lie I.

The procedure of Example 4 is followed, substituting for the 9a-fluoro-l1,8,2l-dihydroxy-l6fi-methyl-16a,17aepoxy-1,4-pregnadiene-3,ZO-dione 21 acetate, an equivalent quantity of 16a,l7a-epoxy-3a-acetoxy-16B-methylpregnene-1l,20-dione, to yield 3a-acetoXy-l7a,hydroxy- 16-methylenepregnane-l 1,20-dione.

Example 13 and To a stirred solution of 500 mg. of 3a-acetoxy-17a-hydroxy-l6-methylene pregnane-11,20-dione in 15 ml. of methylene chloride at 0 C. are added 8 g. of disodium hydrogen phosphate and 2 ml. of 2 M peroxytrifluoroacetic acid in methylene chloride. After 10 minutes at 0 C. and 25 for one hour, water is added and the mixture thoroughly extracted with methylene chloride.

The latter extract is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent and crystallization of the residue from acetone-ether gives a mixture of 3a-acetoxy- 17a-hydroxy-16-spiroepoxy-methylene pregnane 11,20- dione and 3a-acetoxy, 16a,17a-epoxy-l6,8-hydroxymethylpregnane-l1,20-dione. This mixture is separated into its constituents by chromatography on 20 g. of neutral alumina, from which the 16-spiroepoxymethylene compound is eluted first, using benzene and chloroform, followed by the 16u,17a epoxy 16a hydroxymethyl compound.

2% Example 14 The procedure of Example 6 is followed using 3aacetoxy-16a,l7a-epoxy hydroxymethyl-pregnane- 11,20-dione (one of the products of Example 13) in place of the starting material used in Example 6 in equivalent quantities. The product obtained is 3a-acetoxy-16a,17aepoxy-16p-methoxymethylpregnene-1 1,20-dione.

Example 15 $0 ---0H ogt T0110 on,

Example 16 to O== 532120011; 05 i and The procedure of the first paragraph of Example 8 is followed, substituting for the product of Example 7 used there as a starting material. An equivalent quantity of the analogous mixture of A -16methoxy-methyl and 16- methoxymethylene compounds produced in Example 15. The resulting mixture of 3a,17e-dihydroxy-16a and flmethoxymethyl pregnane-ILZO-dioneg is separated by paper chromatography as described in Example 7.

Example 17 O OHRO CH3 To a stirred solution of 1.60 g. of l6oa-methoxymethyl- 3a,17a-dihydroxy-pregnane-11,20-dione (the product of Example 16) in 32 ml. of chloroform, maintained at 3il- 35 C., is slowly added 840 mg. of bromine in 48 m1. of chloroform. Uptake of bromine is complete Within 3 hours. Ether is added and the mixture Washed twice with cold potassium bicarbonate solution. The organic extract is dried over magnesium sulfate and the residue crystallized from acetone-ether to give 16a-Inethoxymethyl-Zl-bromo 306,170: dihydroxy pregnane 11,20- dione. The lop-methyl epimer is prepared similarly.

Example 18 CHzOAe to I on o TN 01120 on.

Example 19 OHzO Ac To a solution of 600 mg. of lfiu-methoxymethyl- 3a,17oc,2 l-trihydroxy-pregnane 11,20 dione 21 acetate (the product of Example 18) in 16 ml. of acetic acid is added 284 mg. of sodium dichromate in 13 ml. of acetic acid. After 17 hours at 25 C., 50% saturated aqueous sodium chloride solution is slowly added. The precipitated product is filtered, washed with water, dried 26 in air and recrystallized from acetone-ether to give 16w methoxymethyl-17a,2 1-dihydroxy-pregnane-3 ,1 1,20-trione Z1-acetate. The l6fl-methyl epimer is prepared similarly.

To a stirred solution of 630 mg. of 16a-methoxymethyl-17a,21-dihydroxy-pregnane-3,11,20-trione 21-acetate (the product of Example 19) in 10 ml. of acetic 2O acid and 8 ml. of chloroform kept at 1(] C. is added 240 mg. of bromine in 6 ml. of chloroform. After addition is complete, 1.2 g. of sodium acetate in 7 ml. of cold Water is added. Additional water is added and the mixture is extracted with chloroform. The chloroform extract is Washed with dilute potassium bicarbonate, Water, and dried over sodium sulfate. The residue is triturated with ether to give crystalline -4-bromo-16umethoxymethyl-l7a,21-dihydroxy-pregnane-3,11,20-trione 21-acetate. The l6fi-methyl epimer is prepared similarly. 30

Example 21 C Hz 0 A0 "O H 0- 1W ornoorr. 4.0

NHrCO-NH-N Example 22 omo A0 500 mg. of the semicarbazone of 16u-methoxymethyl- 170:,21 dihydroxy-4-pregnene-3,l1,20-trione 21 acetate (the product of Example 21) is dissolved in 20 ml. of acetic acid, 1.5 ml. of pyruvic acid and 5 ml. of water. After 18 hours at 25 C., Water is added and the mixture is extracted with chloroform.

The chloroform extract is washed with aqueous bicarbonate, water, and dried over sodium sulfate. Removal of the solvent gives 16a-methoxymethyl-17a,21-dihydroxy-4- pregnene-3,ll,20-trione 21-acetate which is purified by recrystallization from acetone and ether. The I6fl-methyl aoeaaae Example 23 CHHOH -011 H 1 M 01170 on, o=c

The ll-carbonyl group of the products of Example 22 is converted to an llfi-hydroxyl group by the procedures of N. L. Wendler, Huang-Minlon and M. Tishler, I. Am. Chem. Soc. 73, 3818 (1951) and R. E. Jones and S. A. Robinson, J. Org. Chem. 21, 586 (1956) in which the 3 and ZO-carbonyl groups are protected as the 3,20-bissemicarbazone, the ll-keto group is reduced by sodium borohydride or lithium borohydride and the semicar bazone protecting groups are removed by treatment with aqueous acetic acid-pyruvic acid. Among the products of this sequence of reactions are 16a-methoxymethylhydrocortisone, 16,8-methoxymethyl-hydrocortisone and other 160: or 16,8-alkoxy alkyl hydrocortisone analogs. The corresponding 21-acetates are prepared by treatment of the 21-a1cohols with acetic anhydride and pyridine at 25 for 17 hours.

Example 24 CHzOAc Halogen at position 9 is introduced into the products of Example 23 by the procedures of I. Fried and E. F. Sabo, J. Am. Chem. Soc. 75, 2273 (1953) and R. F. Hirschmann, R. Miller, J. Wood and R. E. Jones ibid., 78, 4956 (1956) involving formation of the 9,11-olefin, the 11B-hydroxyl-9u-bromo compound, the 95,11B-oxide and the 11B-hydroxyl-9a-fluoro or 9OL-ChlOrO compounds. Among the products of this sequence are 16a-methoxymethyl 9oz-fl11010 hydrocortisone Zl-acetate, l6 S-methoxymethyl 9a-fluoro hydrocortisone 21-acetate and other 16a and l6fl-alkoxy-alkyl 9oz. halo hydrocortisone analogs. The 2l-alcohols are prepared by treatment with aqueous methanolic potassium bicarbonate as described in Example 9. The corresponding ll-ketones are prepared by treatment with sodium dichromate in acetic acid as described under Example 19.

Example 25 (EH20 Ac I --on To a solution of mg. of 9oi-fluoro-l6-methoxymethylene 11,8,1704 21,trihydroxy 1,4 pregnadiene- 3,20-dione ZI-acetate (prepared in Example 7) in 2 m1. of acetone is added 0.5 ml. of concentrated hydrochloric acid. The mixture is kept at 50 for 30 minutes and concentrated to dryness under vacuum to give a residue which is recrystallized from ethylacetate-ligroin to give 9oc-fluOIO- 16 formyl 11fl,l7oz,21 trihydroxy 1,4 pregnadiene- 3,20-dione 21-acetate.

Similarly, when the other 16-methoxymethylene compounds prepared in Example 7 are used instead of the above compound the corresponding 16-formyl compound is obtained. When other 16-(1-methoxy-alkylidene) compounds are used instead, the product is a 16-alkanoyl steroid of corresponding chain length.

Example 26 4 mpg CHeORn in which R is selected from the group consisting of keto. oxygen and ,B-hydroxyl, R is selected from the group consisting of hydrogen and lower alkanoyl, R is selected from the group consisting of hydrogen and lower alkyl, X is selected from the group consisting of hydrogen and halogen, and the dotted line in ring A indicates that the C -C bond is selected from the group consisting of single and double bonds.

2. The compound of the structure CHnOH lection from the group consisting of 'a and 5 substituents.

13. A compound of the formula in which R is selected from the group consisting of hydrogen and lower alkyl.

15 14. The compound of claim 13 in which R is hydrogen.

15. Compounds of the formula CHaO R2 in which R; is selected from the group consisting of kcto CHnORz in which R is selected from the group consisting of keto oxygen and fl-hydroxyl, R is selected from the group consisting of hydrogen and lower alkanoyl, R is selected from the group consisting of hydrogen and lower alkyl, R; is lower alkyl, X is selected from the group consisting of hydrogen and halogen, and the dotted line in ring A indicates that the C C; bond is selected from the group consisting of single and double bonds.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,068,224 December 11, 1962 David Taub et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 28, lines 43 to 52, the formula should appear as shown below instead of as in the patent:

column 32, lines 10 to 19, the formula should appear as shown below instead of as in the patent:

Signed and sealed this 24th day of December 1963,,

(SEAL) Attest:

ERNEST W, SWIDER EDWIN L. REYNOLDS Attesting Officer Acting Commissioner of Patents 

9. A COMPOUND OF THE FORMULA 